ABSTRACT/SUMMARY Antiretroviral therapy (ART) has significantly reduced the mortality of HIV disease and brought viral loads in HIV patients to below detection limits (<50 copies/ml plasma). This has been critical in controlling HIV spread and there is substantial clinical evidence that zero HIV transmissions occur from HIV-infected people with non-detectable viral loads. However, side-effects and non-adherence to the compulsory daily treatment regimen limit the long-term use of ART in infected people. A foreseeable problem with antiretroviral non- adherence is the impact on non-detectable viral loads. We hypothesize that new drugs with improved pharmacological properties, and a long-acting parenteral formulation of antiretroviral drugs that could reduce the dosing to weekly, monthly, or even longer periods of time can significantly impact patient non-adherence. In recent work, we have developed a novel class of picomolar Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with enhanced pharmacological properties, drug resistance profiles, and a wide margin of safety relative to the current FDA approved NNRTIs such as efavirenz and rilpivirin. Because of these novel properties, these new NNRTIs are particularly well-suited for coupling with sustained-release drug delivery technologies. A long-acting nanoformulation of our candidate NNRTI, a naphthyl catechol phenyl ether called Compound I, maintained sustained plasma levels and antiretroviral efficacy for ?3 weeks in HIV-1-infected humanized mice, confirming potential as a late-stage preclinical candidate. Given the favorable pharmacological properties and potent synergy of Compound I with other classes of currently approved FDA drugs, our overall objective is to develop Compound I as a component of long-acting combinatorial ART (cART). We envision long-acting formulations made from different biocompatible biodegradable polymers [PLGA, poly(PDL-co-DO)] that can be delivered as an intramuscular (i.m.) injection of microparticles or a subdermal biodegradable implant to provide sustained-release of NNRTIs in combination with other ARV classes over a period of months to a year. This would be similar to the FDA-approved Lupron Depot, an 8 micron microparticle, (marketed by AbbVie and manufactured by Takeda) that provides multi-months of sustained release of the synthetic hormone, leuprolide acetate for treatment of prostate cancer and endometriosis. The aims of this application are to develop, optimize and test efficacy of Compound I as a component of long-acting cART for pre-exposure prophylaxis (PrEP) as well as late stage therapy in HIV- infected humanized NSG mice. These approaches and techniques will directly benefit patients for the treatment of HIV-1.